Cyclosporine (CsA) is a potent immunosuppressive drug that paradoxically elicits a T lymphocyte dependent autoimmune disease when administered after syngeneic/autologous bone marrow transplantation. This autoaggression syndrome which develops 2-4 weeks after withdrawal of CsA therapy was termed syngeneic graft-vs-host disease (SGVHD) because its similarity (histologically, target organs) to acute and chronic GVHD occurring after allogeneic BMT. This autoimmune syndrome has an initial onset of an acute phase of disease with a CD8+ T lymphocytic infiltrate in the epidermis followed by progression to a more chronic type syndrome (scleroderma, fibrosis) with predominantly CD4+ T cells in the dermis. The development and progression of disease appears related to the requisite interaction of two distinct autoreactive T cell subsets. Further studies have identified two important mechanisms in the pathogenesis of this autoimmune disease: the apparent enhanced production of CD4+ and CD8+ class II specific autoreactive cells and the elimination of a peripheral host resistance or autoregulatory mechanisms involved in syngeneic GVHD, both the acute and chronic phases. The first goal is to characterize the in vivo effector mechanisms by adoptive transfer studies in which the CD4+ and CD8+ subsets isolated during the acute and chronic phases will be transferred singly or recombined from different disease states, into secondary recipients to assess if the acute and chronic phases of disease are mediated by distinct subsets or if both subsets are required conjointly. The role of cytokines (IL-2, IL-4, IL-6, gamma-interferon) in this disease process will also be evaluated to determine their role in the pathogenesis of disease. Further, in vitro studies will identify and characterize the specificity of these effector mechanisms by limiting dilution analysis and by use of cloned T cell populations. The potential of autoreactive cells in normal animals to mediate syngeneic GVHD or collaborate with CD4+ and/or CD8+ effector subsets from autoimmune donors will also be assessed. The second major goal is to characterize the peripheral autoregulatory mechanism which controls the development of syngeneic GVHD in vivo. Adoptive transfer studies will be utilized to assess the specificity of this autoregulatory system in vivo and to further characterize the age dependent development of this system. This autoregulatory system may also control the induction of this syndrome through a more central mechanism. Studies will be undertaken to determine the role of T lymphocytes derived from the marrow of older animals which modifies the induction of autoimmune disease with particular reference to the generation of autoreactive cells in the thymus. Further, we will also determine if the CD4+ and CD8+ subsets of effector cells are the target(s) of this autoregulatory mechanism. These studies will define some of the immunobiological mechanisms involved in this autoaggression syndrome and identify normal control mechanisms which prevent disease manifestation.